Glioblastoma (GBM), the most common type of primary brain tumor, is an aggressive, highly invasive and neurologically destructive tumor considered to be among the deadliest of all human cancers. While it is known that GBM are tumors of glial origin, a continuing and intense debate surrounds whether they arise from differentiated astrocytes, committed astrocyte progenitors or undifferentiated neural stem cells (NSC). The identification of NSC in adult brain has stimulated speculation that poorly differentiated GBM may result from transformation of a NSC or early glial progenitor, rather than progressive dedifferentiation of a mature astrocyte. Distinction among these possibilities may be important in predicting the probable genetic targets involved in malignant transformation and tumor progression. Indeed, the state of glial cell differentiation may be an important factor that governs whether a given genetic mutation exerts its full oncogenic potential. Along these lines, it is possible that there may exist fundamental differences between NSC and astrocytes with regard to the number and types of mutations needed for each cellular compartment to reach a critical cancer threshold of genetic changes for malignant transformation. The major goal of this proposal is to test the hypothesis that both the neural stem cells and terminally differentiated astrocytes are sensitive to malignant transformation by GBM relevant mutations. To test this hypothesis we will use a new generation of transgenic mice which permit temporal control over targeting single or multiple mutations specifically to either NSC or astrocytes and allow the progeny of transformed cells to be traced over time as the tumor progresses. We will perform detailed histological, immunohistochemical and molecular analysis of mouse NSC and astrocyte derived tumors as well as similar analysis of primary human GBM tumors. We anticipate that this information will provide essential insight into GBM tumor cells and their normal cellular counterparts in the brain and that this information will be crucial for generating accurate, faithful mouse models of the disease. PUBLIC HEALTH RELEVANCE: GBM is the deadliest of common human malignancies. The results of these studies could be used to develop new screening tests for GBM cancer, new diagnostic aids, new predictors of outcome and may help identify new targets for chemotherapy and treatment.